tbuckley/cabot-search huggingface dataset:
Abstract 2450: Investigating the intrinsic and extrinsic factors regulating breast cancer dormancy
Authors: Qihao Ren, Weng Hua Khoo, Jiayu Ye, Douglas V. Faget, Peter I. Croucher, Sheila A. Stewart
Journal: Cancer Research (2022)

Abstract Unfortunately, breast cancer can recur in patients upwards of 25 years after an initial diagnosis and “cure”. It was once thought that recurrence occurred within patients that harbored dormant breast disseminated tumor cells (DTCs) in distant organs that were not present in patients that did not recur. Interestingly, a significant percent of patients harbor DTCs, yet many do not recur, raising the critical question, what differentiates patients that experience a recurrence versus those who live with dormant DTCs for the rest of their lives? It is likely the answer lies in both cell intrinsic as well as extrinsic factors. Nevertheless, the extreme rarity of dormant DTCs has been the major obstacle to their study. To overcome this challenge, we developed an efficient system to isolate and study rare dormant tumor cells from metastatic organs. Using this system and single cell RNA-sequencing (scRNA-seq), we identified a group of genes differentially expressed in dormant breast cancer cells present in both bone and lung. While modulation of these genes individually had no impact on the metastatic behavior of breast cancer cells, we found that as a group, these genes predicted the dormancy phenotype in murine breast cancer models. Importantly, expression of these genes in primary human breast cancer tumors correlated with disease-free survival, suggesting these genes have predictive value in determining which patients are likely to recur. Moreover, we explored extrinsic mechanisms that impact dormancy and found that the chemotherapy reagent doxorubicin (Doxo) drastically changed the microenvironment in vivo, which allowed dormant breast cancer cells to grow robustly within the visceral fat and this was further exacerbated by a high fat diet. Further, we found that Doxo treatment induces significant adipose tissue dystrophy and macrophage infiltration, which may contribute to dormant metastatic outgrowth. Our study provides novel insight into breast cancer dormancy, and also reveals microenvironmental changes that impact dormant breast cancer cell outgrowth. Citation Format: Qihao Ren, Weng Hua Khoo, Jiayu Ye, Douglas V. Faget, Peter I. Croucher, Sheila A. Stewart. Investigating the intrinsic and extrinsic factors regulating breast cancer dormancy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2450.
Abstract LB004: Upregulation of STAT3 signaling in tumor cells fosters a TME-dependent secondary resistance of BRCA1-deficient HGSOC to PARP inhibition
Authors: Liya Ding, Qiwei Wang, Michael Kearns, Tao Jiang, Xin Cheng, Changli Qian, Jean Zhao
Journal: Cancer Research (2022)

Abstract PARP inhibitors (PARPi) have demonstrated potent therapeutic efficacy in patients with ovarian cancer. However, acquired resistance to PARPi is a major challenge in the clinic. Therefore, understanding the resistance mechanism and developing new treatment approaches are important to overcome therapeutic resistance to PARP inhibition. By using our GEM of Brca1-deficient ovarian tumor model, we uncovered a new mechanism underlying a secondary resistance to PARP inhibition mediated by tumor associated macrophages (TAMs) in the tumor microenvironment (TME). Mechanistically, PARP inhibition induced the STAT3 signaling pathway in tumor cells, which in turn promoted pro-tumor polarization of TAMs in the TME of ovarian cancer. Ablation of STAT3 in tumor cells mitigated polarization of M2-like pro-tumor macrophages in the TME and increased tumor infiltration T cells in response to PARP inhibition. Furthermore, we demonstrated that STING agonists reprogramed myeloid cells in the TME of ovarian tumor into antitumor M1-like macrophages and activated dendritic cells (DCs) in a myeloid cell STING-dependent manner. These findings were recapitulated in patient-derived PARPi-resistant ovarian tumor models. Finally, we show that STING agonism was able to overcome the secondary resistance to PARPi in ovarian cancer rendered by immunosuppressive TME. Our study elucidates a new mechanism of PARPi resistance and provides a new treatment strategy to overcome the TME-induced therapeutic resistance to PARP inhibition in ovarian cancers. Citation Format: Liya Ding, Qiwei Wang, Michael Kearns, Tao Jiang, Xin Cheng, Changli Qian, Jean Zhao. Upregulation of STAT3 signaling in tumor cells fosters a TME-dependent secondary resistance of BRCA1-deficient HGSOC to PARP inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB004.
Abstract 2412: Emergence of resistance to MTI-101 selects for favorable MET phenotype in lung cancer
Authors: Clark Jones, Lori Hazlehurst
Journal: Cancer Research (2022)

Abstract Lung cancer remains the most-deadly of all cancers, and thus clinical evidence indicates novel treatment strategies are needed to improve patient outcomes. Our laboratory has been developing a novel cyclic peptide coined MTI-101, which induces cell death via calcium overload, a finding dependent on the TRPC1/TRPC5/TRPC4 complex. To better understand determinants of sensitivity and resistance to MTI-101, we developed drug resistant isogenic lung cancer cell lines. Two isogenic drug resistant cell lines were generated with chronic exposure to MTI-101 in PC-9 (NSCLC EGFR Driven) and H446 (SCLC PTEN Deleted and c-MYC amplified). Drug resistance was confirmed in both cell lines with over two-fold increases in IC50 values upon treatment with MTI-101 in MTT assays. Interestingly, pushing the resistant levels beyond a two-fold increase was not obtained as cultures did not sustain growth with increased selection pressure. Using the isogenic systems coupled with RNA-SEQ, the top enriched GSEA hallmark was downregulation of genes that contribute to EMT in both MTI-101 resistant lines. The RNA-SEQ data correlated with changes in the phenotype which included a significant decreased invasion in Matrigel and changes of MET markers (E-Cadherin, Vimentin) at the protein level. Furthermore, in the EGFR driven PC-9 cell line, selection for resistance towards MTI-101 resulted in collateral sensitivity to EGFR inhibitors. To determine the stability of the MET phenotype, cells were removed from drug, then tested for invasion and drug resistance every month. Our data indicated that the MET phenotype and genotype was stable for a minimum of six months. RNA-SEQ data continued to demonstrate decreased expression of EMT in cells removed from drug compared to the parental cell line. MTI-101 treatment in PC-9 and H446 cells showed synergistic activity with standard of cares Erlotinib, Osimertinib, and Cisplatin when used in combination on the wildtype cells as well. Finally, in vivo data indicates that MTI-101 treatment selects for increased E-Cadherin and decreased Vimentin. Similar to the cell line model, this finding correlated with decreased incidence of bone metastasis in the PC-9 in vivo model. Together our data indicate that MTI-101 treatment could be used as a tool to delay the emergence of resistance and potentially inhibit or delay the emergence of metastatic disease for the treatment of lung cancer. Citation Format: Clark Jones, Lori Hazlehurst. Emergence of resistance to MTI-101 selects for favorable MET phenotype in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2412.
Abstract 1710: Spatial transcriptomics and multiplexed imaging to explore tumor heterogeneity and immune complexity
Authors: Siqi Chen, Andrew Shinkle, Yanyan Zhao, Chia-Kuei Mo, Andrew Houston, Preet Lal, John M. Herndon, Ryan C. Fields, William Gillanders, Feng Chen, Li Ding
Journal: Cancer Research (2022)

Abstract Spatial transcriptomics (ST) and CO-Detection by indEXing (CODEX) are becoming the leading transformative approaches for studying spatially resolved tumor heterogeneity and immune complexity. To explore the application of these two cutting-edge technologies and to further investigate the complexities of tumor microenvironment, we applied 10x Visium Gene Expression platform and Akoya CODEX platform on surgical resections from pancreatic ductal adenocarcinoma (PDAC), breast cancer (BRCA), and clear cell renal carcinoma (ccRCC) patients. A total of 30+ protein markers were screened, verified, and conjugated as CODEX antibodies for the 3 types of cancers. Tumor microenvironment was vividly revealed by a set of cancer markers, immune markers, and stroma cells markers on a single ST slide and a single CODEX image. Notably, the distinct immune microenvironment was observed between tumor nests in the neighborhood in terms of cell types, number of cells, and cell distribution patterns. This work highlights the importance of direct visualization for tumor heterogeneity. It also provides a significant insight for understanding tumor complexity and a promising opportunity to benefit personalized medicine. Citation Format: Siqi Chen, Andrew Shinkle, Yanyan Zhao, Chia-Kuei Mo, Andrew Houston, Preet Lal, John M. Herndon, Ryan C. Fields, William Gillanders, Feng Chen, Li Ding. Spatial transcriptomics and multiplexed imaging to explore tumor heterogeneity and immune complexity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1710.
Abstract 5035: Q-omics: smart software for assisting oncology and cancer research
Authors: Sukjoon Yoon, Euna Jeong, Sumin Jeong, Jieun Lee, Youngju Kim
Journal: Cancer Research (2022)

Abstract Increased multi-level omics data has enabled data-driven studies on cancer drugs, targets and biomarkers. Thus, it is necessary to develop comprehensive tools for oncologists and cancer scientists to carry out extensive data mining without computational expertise. For this purpose, we have developed innovative software that enables user-driven analyses on cancer omics data, assisted by knowledge-based smart systems. Publicly available multi-level omics data of mutations, gene/protein expression, patient survival, immune score (tumor infiltrating cells), drug screening and RNAi (shRNA and CRISPR) screenings on patient samples and cell lines, were integrated from the TCGA, GDSC, CCLE, NCI and DepMap databases. Q-omics provides user-friendly interface for calculation and visualization of cross-associated data pairs retrieved from integrated datasets. The optimal selection of samples, datasets and/or other filtering options is guided by knowledge-bases of the software for the quick and easy finding of significant associations between data pairs. Furthermore, implemented smart algorithms prioritize significant hits based on consensus scoring methods. Consensus scoring using multiple statistical tests with varied sample (or lineage) selection, enriches noise-free, robust cross-associated pairs in the hit list. We believe that Q-omics provide simple but powerful tools for all areas of oncology and cancer research. The latest version of Q-omics software is available at http://qomics.sookmyung.ac.kr. Citation Format: Sukjoon Yoon, Euna Jeong, Sumin Jeong, Jieun Lee, Youngju Kim. Q-omics: smart software for assisting oncology and cancer research [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5035.
Abstract LB015: CCR7-expressing T-cell acute lymphoblastic leukemia mouse model provides a platform for developing novel anti-CCR7 therapies to prevent CNS invasion
Authors: Angel Torres, Aaron Vazquez, Sean Glenn, Zenaida Fuentes, jessica Chacon, Colin Bill, Charlotte M. Vines
Journal: Cancer Research (2022)

Abstract C-C chemokine receptor 7 (CCR7) plays a pivotal role in promoting the migration of T-cell acute lymphoblastic leukemia (T-ALL) cells into the central nervous system during leukemogenesis. Overexpression of CCR7 has also been linked to developing central nervous system (CNS) lymphoma. CCR7 and its ligand, CCL19 are important mediators in the development of these cancers. Thus there is an urgent need for a translational syngeneic CCR7-expressing T-ALL model that can speed up the discovery of drugs that can be used to block CCR7 function during the progression of T-ALL. Using the established ROSA26 floxed-stop Prdm14 (R26PR)/Mx-1 Cre mouse T-ALL model we have initiated studies using a CCR7/CCL19 antagonist, ELC8-83 to examine the molecular mechanisms that mediate CCR7-directed migration to, invasion of, proliferation within and exit from the CNS. mRNA expression of CCR7 in the T-ALL was confirmed by RT-PCR and protein expression on the cell surface was confirmed by flow cytometry. Chemotaxis and calcium mobilization of T-ALL in response to CCL19 was confirmed using transwell-migration assays and FURA-4. ELC8-83 was used to block this signaling. These studies demonstrate the efficacy of ELC8-83 in blocking signaling in T-ALL and provide a platform for testing ELC8-83 in the mouse model of T-ALL. Citation Format: Angel Torres, Aaron Vazquez, Sean Glenn, Zenaida Fuentes, jessica Chacon, Colin Bill, Charlotte M. Vines. CCR7-expressing T-cell acute lymphoblastic leukemia mouse model provides a platform for developing novel anti-CCR7 therapies to prevent CNS invasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB015.
Abstract 2155: PMR-116, a novel inhibitor of ribosome biogenesis with antitumor activity in preclinical models of prostate cancer
Authors: Alisee Huglo, Richard Rebello, Mitchell Lawrence, Gail Risbridger, Denis Drygin, Mustapha Haddach, Katherine Hannan, Ross Hannan, Luc Furic
Journal: Cancer Research (2022)

Abstract Advanced prostate cancer is characterised by mutations and amplifications of genes involved in regulating protein synthesis. PTEN-loss stimulates activity of the mTOR pathway, while amplification of MYC leads to increased ribosome biogenesis and elevated mRNA translation rate. Our previous work has demonstrated the efficacy of co-targeting ribosome biogenesis, via inhibition of RNA Pol I activity, and 4E-BP1 phosphorylation to suppress prostate cancer growth in vivo in GEMM of PCa and in patient-derived xenografts (Rebello et al., Clinical Cancer Research, 2016; Lawrence et al., European Urology, 2018). In a collaboration with Pimera Inc., we investigated the efficacy of their new lead RNA Pol I inhibitor PMR-116 in models of prostate cancer. PMR-116 is well tolerated in vivo in mice and can be given at 300mg/kg weekly. Using the Hi-MYC mouse model of PCa we show that dosing 6 month old mice once weekly for 4 weeks can decrease the incidence of invasive lesions by up to 85% compared to vehicle control while reverting glands to patterns of low grade intraepithelial neoplasia. PMR-116 rapidly inhibits proliferation in the Hi-MYC model with a 50% decrease in Ki67 observed 12 hours after oral administration. Conversely, PMR-116 showed minimal anti-tumour efficacy in the PTEN-null model of PCa suggesting that elevated MYC signalling may be required for optimal response. To further validate our promising GEMM results in more clinically relevant human-derived models, we used patient-derived xenografts lines we established from multidrug-resistant, metastatic PCa (Lawrence et al, European Urology, 2018). PMR-116 treatment decreased tumour volume in all PDX tested including complete response in a line in which tumour volume decreased by ~90% compared to baseline. We believe this new RNA Pol I inhibitor shows promising results in a wide range of preclinical models and may exert higher efficacy in tumours expressing high levels of MYC. PMR-116 is currently in Phase I dose escalation trial in patient with solid tumours (ACTRN12620001146987). Citation Format: Alisee Huglo, Richard Rebello, Mitchell Lawrence, Gail Risbridger, Denis Drygin, Mustapha Haddach, Katherine Hannan, Ross Hannan, Luc Furic. PMR-116, a novel inhibitor of ribosome biogenesis with antitumor activity in preclinical models of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2155.
Abstract 4098: Comparison of frontline therapeutic modalities in stages I/IE extranodal NK/T-cell lymphoma-nasal type (ENKTL-N): A network meta-analysis
Authors: Philip A. Haddad, Kevin Gallagher, Dalia Hammoud
Journal: Cancer Research (2022)

Abstract Introduction: Despite many studies reporting on the optimal therapies for early stage ENKTL-N in the front-line setting, this area continues to be subject to significant controversy regarding single modalities versus combination or sequential approaches. All these comparative studies were small non-randomized studies that combined stages I &amp; II. The results were often inconclusive and occasionally conflicting. In the absence of direct head-to-head randomized controlled trials in this clinical setting, a network meta-analysis was conducted to compare these therapeutic approaches and their respective impact on 5-year survival in stage I/IE ENKTL-N. Methods: A review of the medical literature was conducted using online databases. Inclusion criteria consisted of English language, diagnosis of stage I/IE ENKTL-N, treatment with chemotherapy (CT), radiation (RT), sequential CT and RT (SEQ), and chemoradiotherapy (CRT), comparative studies that reported predominantly I/IE 5-year survival and disease-free survival rates. Studies that reported on mixed samples of early and advanced ENKTL were excluded. A frequentist network meta-analysis was conducted using the netmeta package and random-effects model. Results: Seven studies comprising a total of 377 participants were included. Our network meta-analysis revealed that upfront RT tended to have better 5-year OS and DFS than CRT and SEQ, though it did not reach statistical significance. However, RT demonstrated significant 5-year OS and DFS when compare to CT alone in the frontline setting. Based on the pairwise and network meta-analyses, RT was ranked as the most effective first-line treatment approach followed by CRT, SEQ, and CT in decreasing order. Inconsistency analysis did not reveal any significant differences between direct and indirect estimates. Conclusions: This is the first network meta-analysis to compare all commonly utilized upfront treatment modalities in stages I/IE ENKTL-N. It indicates that upfront RT alone may be sufficient as there was no signal that chemotherapy added any OS or DFS advantages. Adequately powered randomized trials are warranted. Citation Format: Philip A. Haddad, Kevin Gallagher, Dalia Hammoud. Comparison of frontline therapeutic modalities in stages I/IE extranodal NK/T-cell lymphoma-nasal type (ENKTL-N): A network meta-analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4098.
Abstract 5807: MDM2 mitochondrial translocation mediates metabolic reprogramming towards OXPHOS in TKI-resistant oncogene-addicted cancer
Authors: Jie Qing Eu, Li Ren Kong, Jayshree Hirpara, Boon Cher Goh, Andrea LA Wong, Shazib Pervaiz
Journal: Cancer Research (2022)

Abstract There is mounting evidence of oxidative phosphorylation (OXPHOS) dependency in cancers resistant to tyrosine kinase inhibitors (TKI), but the cause of this metabolic switch remains elusive. Mitochondria-bound MDM2 (mtMDM2), the fraction of MDM2 oncoprotein which is actively imported into the mitochondria, has been found to dysregulate electron transport chain (ETC) complex I function and OXPHOS. AKT is known to be a regulator of MDM2 protein stability. Given that AKT phosphorylation is commonly detected in oncogene-addicted tumours, we investigated the role of mtMDM2 and AKT in promoting TKI resistance through reprogrammed cellular metabolism. EGFR+ NSCLC [HCC827 and HCC827-GR (gefitinib-resistant)] and BRAF+ melanoma [A375 and A375-VR (vemurafenib-resistant)] cells were established via repetitive pulsed strategy. Translocation of MDM2 was examined through subcellular fractionation and Western Blotting. To investigate the role of MDM2 in mediating OXPHOS, genetic knockdown of MDM2 was performed via siRNA followed by measurement of oxygen consumption rate (Seahorse Analyzer); mRNA expression of mtDNA-encoded ETC subunits by real-time PCR (qPCR). ChIP-qPCR analysis was performed to examine the binding affinity of MDM2 and TFAM (mitochondrial transcription factor A) to mitochondrial DNA (mtDNA). Mitochondrial translocation of MDM2 was predominant in TKI-sensitive cells; MDM2 silencing upregulated OXPHOS and induced mRNA expression of mtDNA-encoded ETC complex I subunits, suggesting that mtMDM2 inhibits OXPHOS. ChIP analysis revealed competitive binding of MDM2 and TFAM at the LSP region of mtDNA. Conversely, MDM2 was primarily localized the cytoplasm in TKI-resistant cells and was associated with increased OXPHOS in TKI-resistant cells. Mechanistically, both pAKT and pMDM2 (Ser166/Ser186) were higher in TKI-resistant cells. Collectively, we describe a novel observation that OXPHOS upregulation underpinning TKI resistance in cancer cells could be mediated by AKT upregulation and MDM2 localisation. Citation Format: Jie Qing Eu, Li Ren Kong, Jayshree Hirpara, Boon Cher Goh, Andrea LA Wong, Shazib Pervaiz. MDM2 mitochondrial translocation mediates metabolic reprogramming towards OXPHOS in TKI-resistant oncogene-addicted cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5807.